The candidate is a neurologist/psychiatrist with training in neurobiology, and an assistant professor of psychiatry and neurology at the Washington University School of Medicine (WUStL), a world leading institution in genetics and epidemiology of psychiatric disorders. The candidate's immediate goal is to complete a master's degree in epidemiology and genetics to maximize opportunities afforded by his currently funded research and under the mentorship of Dr. Cloninger and Dr. Goate. His long term goal is to concentrate his research career on the study of the genetic control of the relationship between parkinsonism and schizophrenia. Project. Parkinsonism is highly prevalent in newly diagnosed -untreated- patients with schizophrenia; its presence predicts greater susceptibility to neuroleptic-induced side effects, reduced treatment compliance and poorer outcome. Smoking has a negative association with parkinsonism, whereas hyperechogenicity of the substantia nigra, executive function and working memory deficits, and increased harm avoidance on the temperament and character inventory are all positively associated with motor impairment. These diverse phenotypic manifestations are related to a single neurobiological mechanism, namely decreased dopaminergic function. Studying untreated patients prevents the noise introduced into such phenotypic manifestations by the effects of antipsychotic drugs, and therefore will permit isolation of the genetic signal from environmental noise (represented by treatment). We identified a population with untreated schizophrenia, and collected a pilot sample to study the clinical, neuropsychological and neurological characteristics of patients, their first degree relatives, and culturally appropriate controls. We propose to expand the sample. With the funds of this award we will focus on the clinical characterization of the probands and their siblings as well as of controls and their siblings to investigate the heritability of a composite endophenotype including parkinsonism, smoking, cognitive deficit and hyperechogenicity of the substantia nigra. Towards the end of the award period we will work on an Roi application to study the relationship of the proposed phenotype to quantitative trait loci (QTL). The major relevance of the proposed research lies on the possibility of testing if a neurobiologically well defined set of individual characteristics is genetically determined. Because these deficits possibly predate the onset of psychosis, we believe our strategy might provide tools for early detection and early intervention, possibly leading to prevention of psychosis in subjects at-risk for schizophrenia. Lastly, we anticipate that our research strategy may indicate new ways to study and address the increased vulnerability of schizophrenic patients to nicotine dependence.